Targeted Proapoptotic Peptides Depleting Adipose Stromal Cells Inhibit Tumor Growth
Targeted Proapoptotic Peptides Depleting Adipose Stromal Cells Inhibit Tumor Growth
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DOI：
10.1038/mt.2015.155
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发表时间：
2016-01-01
影响因子：
12.4
通讯作者：
Kolonin, Mikhail G.
中科院分区：
文献类型：
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作者：
Daquinag, Alexes C.;Tseng, Chieh;Kolonin, Mikhail G.
许多癌症的进展与间充质基质细胞（MSC）的肿瘤浸润相关。脂肪基质细胞（ASC）是白色脂肪组织（WAT）中作为脂肪细胞祖细胞和内皮支持细胞的MSC。临床和动物模型研究表明，从WAT动员的ASC被肿瘤招募。由于缺乏特异性地抑制这些细胞的方法，因此缺乏ASC在肿瘤微环境中功能的直接证据。在这里，我们研究了抗蛋白水解的靶向猎人杀伤肽D-WAT的作用，该肽由一个归巢于ASC的环状结构域CSWKYWFGEC和一个促凋亡结构域KLAKLAK组成（2）。使用小鼠骨髓移植模型，我们表明D-WAT治疗特异性地消耗肿瘤基质和血管周围细胞，而不直接杀死恶性细胞或肿瘤浸润性白细胞。在几种小鼠癌模型中，靶向ASC细胞消融减少了肿瘤血管分布和细胞增殖，导致肿瘤坏死、坏死和抑制肿瘤生长。我们还验证了具有促凋亡结构域KFAKFAK（2）的D-WAT衍生物，发现其具有改善的细胞消融活性。我们的研究结果首次证明，ASC作为肿瘤微环境的一个组成部分，支持癌症的进展。我们建议靶向ASC的药物可以开发为补充传统癌症治疗的联合疗法。
Progression of many cancers is associated with tumor infiltration by mesenchymal stromal cells (MSC). Adipose stromal cells (ASC) are MSC that serve as adipocyte progenitors and endothelium-supporting cells in white adipose tissue (WAT). Clinical and animal model studies indicate that ASC mobilized from WAT are recruited by tumors. Direct evidence for ASC function in tumor microenvironment has been lacking due to unavailability of approaches to specifically inactivate these cells. Here, we investigate the effects of a proteolysis-resistant targeted hunter-killer peptide D-WAT composed of a cyclic domain CSWKYWFGEC homing to ASC and of a proapoptotic domain KLAKLAK(2). Using mouse bone marrow transplantation models, we show that D-WAT treatment specifically depletes tumor stromal and perivascular cells without directly killing malignant cells or tumor-infiltrating leukocytes. In several mouse carcinoma models, targeted ASC cytoablation reduced tumor vascularity and cell proliferation resulting in hemorrhaging, necrosis, and suppressed tumor growth. We also validated a D-WAT derivative with a proapoptotic domain KFAKFAK(2) that was found to have an improved cytoablative activity. Our results for the first time demonstrate that ASC, recruited as a component of tumor microenvironment, support cancer progression. We propose that drugs targeting ASC can be developed as a combination therapy complementing conventional cancer treatments.